Direct conversion of primary and secondary carboxylic acids to trifluoromethyl ketones

Article abstract of DOI:10.1016/j.tetlet.2006.11.068

Primary and secondary carboxylic acids were converted in one step to the corresponding trifluoromethyl ketones by treatment with trifluoroacetic anhydride (TFAA) and pyridine in toluene at 60-100 °C followed by hydrolysis/decarboxylation with water at 45

Full text of DOI:10.1016/j.tetlet.2006.11.068

Tetrahedron Letters 48 (2007) 189–192
Direct conversion of primary and secondary carboxylic acids
to trifluoromethyl ketones
Jonathan T. Reeves,* Fabrice Gallou, Jinhua J. Song, Zhulin Tan, Heewon Lee,
Nathan K. Yee and Chris H. Senanayake
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Old Ridgebury Road, PO Box 368,
Ridgefield, CT 06877-0368, USA
Received 20 October 2006; revised 9 November 2006; accepted 10 November 2006
Abstract—Primary and secondary carboxylic acids were converted in one step to the corresponding trifluoromethyl ketones by treat-
ment with trifluoroacetic anhydride (TFAA) and pyridine in toluene at 60–100 °C followed by hydrolysis/decarboxylation with
water at 45 °C.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
unhindered primary acid chlorides (RCH2CH2COCl),
we observed very low yields for sterically demanding pri-
mary acid chlorides, such as 1-adamantane acetyl chlo-
ride (1a; entry 1, Table 1) even after extended reaction
times. On hydrolytic work-up (H2O, 0–20 °C), the
desired ketone 2 was isolated in <5% yield, while carb-
oxylic acid 1b was isolated in >80% yield. In an attempt
to obtain higher conversion, we heated the reaction
mixture at reflux (40 °C, 48 h) followed by hydrolysis/
decarboxylation at 40 °C for 2 h. Although Zard and
co-workers noted the hydrolysis/decarboxylation stage
of the reaction was spontaneous for unhindered sub-
strates, we found heating for 1–2 h proved necessary
for more hindered substrates to effect a complete conver-
sion of intermediates to product. This procedure gave an
improved, albeit still low yield of 2 (entry 2, 31%). A
brief screen of higher boiling alternative solvents showed
methyl tert-butyl ether (MTBE) and toluene performed
equally well as CH2Cl2. Toluene was selected for optimi-
zation studies due to its higher boiling point and desir-
able process safety attributes. Heating 1a in toluene
with TFAA/pyridine at 60 °C for 2 h followed by the
addition of H2O at 0 °C and further heating at 45 °C
for 2 h gave 2 in 80% yield (entry 3).
Trifluoromethyl ketones are important components of
many biologically active compounds.1 The powerful
inductive electron-withdrawing effect of the trifluoro-
methyl group renders these ketones exceptionally elec-
trophilic, and the propensity of trifluoromethyl
ketones to form stable hydrates and related tetrahedral
adducts has been exploited in the design of numerous
enzyme inhibitors.2 Trifluoromethyl ketones are also
valuable intermediates for the synthesis of trifluoro-
methyl-substituted heterocycles and other compounds.1
Recently, we required a practical method for large-scale
preparation of primary and secondary (a-enolizable) tri-
fluoromethyl ketones. Among numerous reported pro-
cedures for the synthesis of these compounds,3 the
method of Zard and co-workers was most attractive in
terms of simplicity and potential scalability.4 This meth-
od involves treatment of primary acid chlorides with tri-
fluoroacetic anhydride (TFAA, 6 equiv) and pyridine
(8 equiv) in dichloromethane (CH2Cl2) at rt and subse-
quent hydrolysis/decarboxylation on addition of water
to give the corresponding trifluoromethyl ketones in
40–86% yield. While this procedure worked well for
Having identified a modified procedure which allowed
for the conversion of sterically hindered primary acid
chlorides to trifluoromethyl ketones, we were curious if
these reaction conditions could effect the conversion of
carboxylic acids directly to trifluoromethyl ketones,
thereby eliminating the need for acid chloride formation.
Keywords: Trifluoromethyl ketones; Carboxylic acids; Trifluoroacetic
anhydride; Decarboxylation.
*
Corresponding author. Tel.: +1 203 778 7703; fax: +1 203 791
6130; e-mail: jreeves@rdg.boehringer-ingelheim.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.068

190
J. T. Reeves et al. / Tetrahedron Letters 48 (2007) 189–192
Table 1. Optimization of reaction conditions for the synthesis of 2
O
O
TFAA, pyridine
solvent, temperature;
H2O, 0-45 oC
X
CF3
1a: X = Cl
1b: X = OH
2
Entry
Substrate
Solvent
Temperature (°C)
Time (h)
Hydrolysis temperaturec (°C)
Yieldd (%)
1a
2a
3a
4a
5b
1a
1a
1a
1b
1b
CH2Cl2
CH2Cl2
PhMe
PhMe
PhMe
20
40
60
60
60
48
48
2
6
8
0
40
45
45
45
<5
31
80
84
82
a 6 equiv TFAA, 8 equiv pyridine.
b 4.5 equiv TFAA, 6 equiv pyridine.
c H2O added at 0 °C, then reaction held at listed temperature for 2 h.
d Isolated yield after chromatography on SiO2.
Zard and co-workers postulate the reaction of acid
chlorides as proceeding through trifluoroacetylation of
ketene-derived pyridinium enolate C (Fig. 1). We
reasoned that treatment of carboxylic acid A with
TFAA/pyridine should generate mixed anhydride B,
which could also form C under the reaction conditions.
Notably, Zard and co-workers reported a single example
of conversion of a sodium carboxylate salt to a trifluoro-
methyl ketone, which likewise should proceed through
the intermediacy of B and C.4a,b Indeed, the subjection
of 1-adamantane acetic acid (1b) to the optimized reac-
tion conditions employed for the corresponding acid
chloride 1a gave 2 in 84% yield (entry 4) after 6 h.
Furthermore, we found that the stoichiometry of the
reagent system could be reduced to 4.5 equiv TFAA
and 6 equiv pyridine (from 6 equiv/8 equiv, respectively)
with only a moderate increase in reaction time and no
significant decrease in the yield (entry 5).
prior to trifluoromethyl ketone formation. In addition,
these conditions allow for the successful reaction of sub-
strates which give low yields (hindered primary sub-
strates) or no reaction (secondary substrates) using the
previously described procedure for acid chlorides.4a,b
The use of inexpensive reagents and readily available,
easily handled carboxylic acids as starting materials
makes this a practical method for accessing enolizable
trifluoromethyl ketones.
2. Experimental
2.1. General procedure
A solution of carboxylic acid (10.0 mmol) in toluene
(25 mL) was treated at rt with TFAA (6.3 mL,
45.0 mmol, 4.5 equiv). The reaction mixture was cooled
to 0–5 °C and treated slowly with pyridine (4.9 mL,
60.0 mmol, 6.0 equiv). The reaction mixture was then
heated at the required temperature (see Table 2) until
starting material was consumed by HPLC or GC analy-
sis. The reaction mixture was cooled to 0 °C, water
(20 mL) was slowly added, and the reaction mixture
was heated at 45 °C for 2 h. After cooling to rt, the lay-
ers were cut, the aqueous phase extracted with MTBE,
and the combined organic layers washed with 1 N
NaOH solution, dried over MgSO4, filtered, and con-
centrated to give the crude product, which was purified
by chromatography on silica gel.
Table 2 presents a survey of the scope of the reaction.
Primary carboxylic acids converted smoothly to trifluo-
romethyl ketones (entries 1–3). The indole N–H func-
tionality could be carried through the reaction (entry
3), presumably undergoing N-trifluoroacetylation in
the first stage of the reaction and subsequent cleavage
during the hydrolysis/decarboxylation stage. We also
found that secondary carboxylic acids could be con-
verted to the corresponding trifluoromethyl ketones
(entries 4–8). This transformation was not possible using
the procedure of Zard and co-workers.4a,b Higher tem-
peratures (75–100 °C) and longer reaction times were
necessary, however, for the conversion of secondary
carboxylic acids.
2.2. 3-Adamantan-1-yl-1,1,1-trifluoropropan-2-one (2)
1
Colorless oil; H NMR (400 MHz, CDCl3) d 2.44 (s,
In conclusion, we have described a simple procedure for
the direct conversion of primary and secondary carb-
oxylic acids to trifluoromethyl ketones. The process
reported here eliminates the need for an additional step
for the conversion of carboxylic acids to acid chlorides
2H), 1.99 (br s, 3H), 1.73–1.64 (m, 12H); 13C NMR
(100 MHz, CDCl3) d 190.6 (q, J = 35 Hz), 115.1 (q,
J = 291 Hz), 48.8, 42.0, 36.5, 34.0, 28.5; HRMS calcd
for C13H16F3O [MÀH]+: 245.1147; found: 245.1163.
2.3. 1,1,1-Trifluoro-4,8-dimethylnon-7-en-2-one (3)
O
O
O
O
pyr.
TFAA
pyr.
R
R
R
1
N
OH
O
CF3
Colorless oil; H NMR (400 MHz, CDCl3) d 5.10–5.06
(m, 1H), 2.70 (dd, 1H, J = 17.9, 5.5 Hz), 2.53 (dd, 1H,
J = 17.9, 7.9 Hz), 2.16–2.08 (m, 1H), 2.05–1.94 (m,
2H), 1.69 (s, 3H), 1.60 (s, 3H), 1.41–1.23 (m, 2H), 0.96
A
B
C
Figure 1. Mixed anhydride pathway to pyridinium enolate C.

J. T. Reeves et al. / Tetrahedron Letters 48 (2007) 189–192
Table 2. Conversion of carboxylic acids to trifluoromethyl ketones
191
TFAA (4.5 eq)
pyridine (6.0 eq)
O
O
PhMe, 60-100 oC;
H2O, 45 oC, 2 h
R
OH
R
CF3
Entry
1
Product
Temperature (°C)
Time (h)
8
Yielda (%)
O
60
82
55
CF3
2
O
2
3
60
60
7
6
CF3
3
O
CF3
78
N
H
4
O
CF3
4
5
75
24
48
63c
5
O
100b
58d
CF3
6
O
6
7
100b
100b
30
48
52
41
CF3
Ph
7
O
CH3(CH2)7
CF3
CH3(CH2)5
8
O
8
60
8
66
CF3
9
a Isolated yield after chromatography on SiO2.
b Reaction heated at 60 °C for 1 h, then at 100 °C for indicated time.
c Ratio of 1,4-anti:1,4-syn = 2.2:1.
d For previous synthesis of 6, see Ref. 3a.
(d, 3H, J = 6.7 Hz); 13C NMR (100 MHz, CDCl3) d
191.2 (q, J = 34 Hz), 132.0, 123.7, 115.5 (q,
J = 290 Hz), 43.4, 36.5, 27.8, 25.6, 25.3, 19.4, 17.6;
HRMS calcd for C11H16F3O [MÀH]+: 221.1153; found:
221.1171.
2.5. 1-(4-tert-Butylcyclohexyl)-2,2,2-trifluoroethanone
(5)
1
Major diastereomer (1,4-anti): Colorless oil; H NMR
(400 MHz, CDCl3) d 3.08–3.05 (m, 1H), 2.21 (d, 2H,
J = 13.6 Hz), 1.70–1.56 (m, 4H), 1.23–1.12 (m, 2H),
1.04–0.97 (m, 1H), 0.83 (s, 9H); 13C NMR (100 MHz,
CDCl3) d 194.2 (q, J = 32 Hz), 115.6 (q, J = 293 Hz),
47.7, 41.0, 32.3, 27.3, 26.6, 23.2; GC–MS: 236 [M]+, 57.
2.4. 1,1,1-Trifluoro-3-(1H-indol-3-yl)propan-2-one (4)
Tan solid; mp (hexanes/EtOAc) 66–70 °C; 1H NMR
(400 MHz, CDCl3) d 8.13 (br s, 1H), 7.50 (d, 1H,
J = 8.0 Hz), 7.37 (d, 1H, J = 8.1 Hz), 7.25–7.21 (m,
1H), 7.18–7.14 (m, 2H), 4.17 (s, 2H); 13C NMR
(100 MHz, CDCl3) d 188.9 (q, J = 34 Hz), 136.0,
126.9, 123.9, 122.7, 120.2, 118.3, 115.9 (q, J = 291 Hz),
111.4, 104.6, 33.3; HRMS calcd for C11H9F3NO
[M+H]+: 228.0630; found: 228.0652.
1
Minor diastereomer (1,4-syn): Colorless oil; H NMR
(400 MHz, CDCl3) d 2.77–2.69 (m, 1H), 2.03 (d, 2H,
J = 12.7 Hz), 1.93–1.90 (m, 2H), 1.46–1.37 (m, 2H),
1.13–1.02 (m, 3H), 0.86 (s, 9H); 13C NMR (100 MHz,
CDCl3) d 194.6 (q, J = 33 Hz), 115.8 (q, J = 292 Hz),
47.0, 45.2, 32.4, 28.4, 27.3, 26.3; GC–MS: 236 [M]+,
57.

192
J. T. Reeves et al. / Tetrahedron Letters 48 (2007) 189–192
2.6. 1,1,1-Trifluoro-3-methyl-4-phenylbutan-2-one (6)3a
0.89 (d, 6H, J = 6.6 Hz); 13C NMR (100 MHz, CDCl3)
d 192.1 (q, J = 33 Hz), 141.7, 134.0, 129.9, 127.7, 115.9
(q, J = 292 Hz), 46.9, 45.0, 30.2, 22.3, 17.9; GC–MS:
258 [M]+, 215, 161.
Yellow oil; 1H NMR (400 MHz, CDCl3) d 7.31–7.27 (m,
2H), 7.24–7.20 (m, 1H), 7.15–7.13 (m, 2H), 3.28–3.21
(m, 1H), 3.10 (dd, 1H, J = 13.7, 6.4 Hz), 2.64 (dd, 1H,
J = 13.7, 7.9 Hz), 1.19 (d, 3H, J = 6.9 Hz); 13C NMR
(100 MHz, CDCl3) d 194.7 (q, J = 33 Hz), 137.9,
128.6, 128.2, 126.8, 115.7 (q, J = 292 Hz), 42.9, 36.9,
15.9; GC–MS: 216 [M]+, 91.
References and notes
´
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(7)
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(b) Walter, M. W.; Adlington, R. M.; Baldwin, J. E.;
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1
Colorless oil; H NMR (400 MHz, CDCl3) d 7.28–7.14
´
´
(m, 5H), 3.73 (d, 1H, J = 10.9 Hz), 2.62–2.52 (m, 1H),
1.88–1.80 (m, 1H), 1.64–1.48 (m, 3H), 1.44–1.28 (m,
2H), 1.10–1.02 (m, 1H), 1.00–0.93 (m, 1H); 13C NMR
(100 MHz, CDCl3) d 191.7 (q, J = 33 Hz), 135.5,
128.8, 128.3, 127.9, 115.8 (q, J = 292 Hz), 58.9, 43.1,
31.5, 30.6, 25.1, 24.5; GC–MS: 256 [M]+, 188, 159, 91.
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nilov, A.; Rodrigues, I.; Richard, C. J. Org. Chem. 1998, 63,
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2.8. 1,1,1-Trifluoro-3-hexylundecan-2-one (8)
1
Colorless oil; H NMR (400 MHz, CDCl3) d 2.95–2.88
(m, 1H), 1.75–1.68 (m, 2H), 1.53–1.46 (m, 2H), 1.30–
1.22 (m, 20H), 0.89–0.86 (m, 6H); 13C NMR
(100 MHz, CDCl3) d 195.6 (q, J = 33 Hz), 115.6 (q,
J = 291 Hz), 46.5, 31.8, 31.5, 31.2, 31.1, 29.5, 29.3,
29.2, 29.1, 27.1, 27.0, 22.6, 22.5, 14.1, 14.0.
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2.9. 1,1,1-Trifluoro-3-(4-iso-butylphenyl)butan-2-one (9)
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1992, 33, 1285–1288; (b) Boivin, J.; El Kaim, L.; Zard, S. Z.
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1
Colorless oil; H NMR (400 MHz, CDCl3) d 7.15–7.12
(m, 4H), 4.16 (q, 1H, J = 6.9 Hz), 2.45 (d, 2H,
J = 7.2 Hz), 1.84 (m, 1H), 1.50 (d, 3H, J = 6.9 Hz),